Skip to main content
SpringerLink
Log in

Effects of Tranexamic Acid and Aprotinin, Two Antifibrinolytic Drugs, on PAF-induced Plasma Extravasation in Unanesthetized Rats

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Two antifibrinolytic drugs, tranexamic acid (TXA), and aprotinin (APR), are currently used to improve the recovery of patients following major surgery while reducing blood loss. Their mechanisms of action have yet to be fully understood. Here, we examined (1) the effects of TXA or APR on basal vascular permeability (VP) and (2) the effects of TXA or APR on platelet-activating factor (PAF)-induced increase of VP in normal unanesthetized rats. Evans blue dye (EB) bound to albumin was used as the marker of extravasation in selected tissues. In normal rats, PAF (1 μg/kg i.v.) increased VP in most selected tissues including bronchi, aorta, duodenum and pancreas without affecting blood pressure. TXA (up to 300 mg/kg i.v.) had no significant effect on basal VP in any tissues, while APR (30 000 KIU/kg i.v.) decreased basal VP in 5 out of 8 tissues. Pre-treatment with TXA decreased PAF-induced increases of VP in the microcirculation of the thoracic and abdominal aorta, the duodenum and the pancreas, from 35% to 41%. TXA was mostly effective at an i.v. dose of 100 mg/kg with a 2 h of pre-treatment period. Pre-treatment with APR also reduced PAF-induced increases of VP in selected tissues by 35 to 61%. The i.v. dose of 30 000 KIU/mg was optimal when injected at least 30 min before the administration of PAF + Evans blue. These results suggest that the beneficial effect of APR and TXA, following cardiopulmonary bypass (CPB) and other type of surgeries, may be attributed to the inhibition of plasma exudation mediated, at least in part, by PAF. Thus, TXA and APR may improve patients recovery by reducting the capillary leakage of albumin, associated with interstitial edema formation, and maintaining intravascular fluid volume.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. KIRKLIN, J. K., E. H. BLACKSTONE, and J. W. KIRKLIN. 1987. Cardiopulmonary bypass: Studies on its damaging effects. Blood Purific. 5:168-178.

    Google Scholar 

  2. WACHTFOGEL, Y. T., U. KUCICH, J. GREENPLATE, P. GLUSZKO, W. ABRAMS, G. WEINBAUM, R. K. WENGER, B. RUCINSKI, S. NIEWIAROWSKI, and L. H. EDMUNDS. 1987. Human neutrophil degranulation during extracorporeal circulation. Blood 69:324-330.

    Google Scholar 

  3. EDMUNDS, L. H. JR, N. ELLISON, R. W. COLMAN, S. NIEWIAROWSKI, A. K. RAO, V. P. ADDONIZIO, L. W. STEPHENSON, and R. N. EDIE. 1982. Platelet function during cardiac operation: Comparison of membrane and bubble oxygenators. J. Thorac. Cardiovasc. Surg. 83:805-812.

    Google Scholar 

  4. MOFFIT, E. A., J. W. KIRKLIN, and R. A. THEYE. 1962. Physiologic studies during whole-body perfusion in tetralogy of Fallot. J. Thorac. Cardiovasc. Surg. 44:180-188.

    Google Scholar 

  5. PAGE, C. P., C. B. ARCHER, W. PAUL, and J. MORLEY. 1990. PAF-aceter: a mediator of inflammation and asthma. Trends Pharmacol. Sci. 5:239-241.

    Google Scholar 

  6. RUBIN, A. H. E., L. J. SMITH, and R. PATTERSON. 1987. The bronchoconstrictor properties of platelet activating factors in humans. Am. Rev. Respir. Dis. 136:1145.

    Google Scholar 

  7. WIRTZ, H., M. LANG, U. SANNWALD, and H. HAHN. 1986. Mechanism of platelet activating factor (PAF) induced secretion of mucus from tracheal submucosal glands in ferret. Fed. Proc. 45:418-421.

    Google Scholar 

  8. WARDLAW, A. J., R. MOQBEL, O. CROMWELL, and A. B. KAY. 1986. Platelet-activating factor: a potent chemotactic and chemokinetic factor for human eosinophils. J. Clin. Invest. 78:1701.

    Google Scholar 

  9. CUSS, F. M., C. M. S. DIXON, and P. J. BARNES. 1986. Effects of inhaled platelet-activating factor on pulmonary function and bronchial hyperesponsiveness in man. Lancet 2:189-192.

    Google Scholar 

  10. ARCHER, C. B., C. P. PAGE, W. PAUL, J. MORLEY, and D. A. MCDONALD. 1984. Inflammatory characteristics of platelet activating factor (PAF-aceter) in human skin. Br. J. Dermatol. 110:45-50.

    Google Scholar 

  11. SIROIS, M. G., G. E. PLANTE, P. BRAQUET, and P. SIROIS. 1990. Role of eicosanoids in PAF-induced increases of the vascular permeability in rat airways. Br. J. Pharmacol. 101:896-900.

    Google Scholar 

  12. GOLDENGERG, M. M., and R. D. MEURER. 1984. A pharmacologic analysis of the action of platelet-activating factor in the induction of hind-paw oedema in the rat. Prostaglandins 28:271-278.

    Google Scholar 

  13. HARDY, J. F., and S. BELISLE. 1994. Natural and synthetic antifibrinolytics in adult cardiac surgery: Efficacy and effectiveness. Can. J. Anaesth. 41:1104-1112.

    Google Scholar 

  14. PUGH, S. C., and A. K. WIELOGORSKI. 1995. A comparison of the effects of tranexamic acid and low-dose aprotinin on blood loss and homologous blood usage in patients undergoing cardiac surgery. J. Cardiothor. Vasc. Anes. 9:240-244.

    Google Scholar 

  15. TRAUTSCHOLD, I., E. WERLE, and G. ZICKGRAF-RUEDEL. 1966. The kallikrein-trypsin inhibitor. Arzeim Forsch 16:1507-1515.

    Google Scholar 

  16. ASTEDT, B. Clinical pharmacology of tranexamic acid. 1987. Scand. J. Gastroenterol. 137:225.

    Google Scholar 

  17. SIROIS, M. G., S. JANCAR, P. BRAQUET, G. E. PLANTE, and P. SIROIS. 1988. PAF increases vascular permeability in selected tissues: Effect of BN-52021 and L-655,240. Prostaglandins 36:631-644.

    Google Scholar 

  18. ROGERS, D. F., P. BOSCHETTO, and P. J. BARNES. 1989. Plasma exudation correlation between Evans blue dye and radiolabeled albumin in guinea-pig airways in vivo. J. Pharmacol. Meth. 21:309-315.

    Google Scholar 

  19. PATTERSON, C. E., R. A. RHOADES, and J. G. N. GARCIA. 1992. Evans blue as a marker of albumin clearance in cultured endothelial monolayer and isolated lung. J. Appl. Physiol. 72:865-873.

    Google Scholar 

  20. MOVAT, H. Z., and N. L. DILORENZO. 1968. Activation of plasma kinin system by antigen-antibody aggregates. I. Generation of permeability factor in guinea-pig serum. Lab. Invest. 19:187.

    Google Scholar 

  21. UDAKA, K., Y. TAKEUCHI, and H. Z. MOVAT. 1970. Simple method for quantitation of enhanced vascular permeability. Proc. Soc. Exp. Biol. Med. 133:1384.

    Google Scholar 

  22. FRIMMER, M., and F. W. MULLER. 1962. Branchbarkeit und grenzen der forbstoffmethoden zur bestimmung vermehrter durchlassigkeitder haut-capillaren. Med. Exp. 6:327-330.

    Google Scholar 

  23. EVANS, T. W., K. F. CHUNG, D. F. ROGERS, and P. J. BARNES. 1987. Effect of platelet-activating factor on airway vascular permeability: possible mechanisms. J. Appl. Physiol. 63:479-484.

    Google Scholar 

  24. SIROIS, M. G., W. T. DE LIMA, A. J. DE BRUM FERNANDES, R. J. JOHNSON, G. E. PLANTE, and P. SIROIS. 1994. Effect of PAF on rat lung vascular permeability: role of platelets and polymorphonuclear leucocytes. Br. J. Pharmacol. 111:1111-1116.

    Google Scholar 

  25. O'DONNELL, S. R., and J. K. BARNETT. 1987. Microvascular leakage to platelet-activating factor in guinea-pig trachea and bronchi. Eur. J. Pharmacol. 138:385-396.

    Google Scholar 

  26. O'BRIEN, J. G., B. BATTISTINI, R. J. JOHNSON, F. ZAHARIA, G. E. PLANTE, and P. SIROIS. 1997. Participation of neutrophils or platelets in the effect of tranexamic acid or aprotinin against bradykinin induced plasma extravasation in conscious rats. Can. J. Physiol. Pharmacol. 75:741-749.

    Google Scholar 

  27. VIOSSAT, I., J. M. GUILLON, E. ETIEMBE, and E. PIROTZKY. 1988. Use of ginkolides on PAF-acether induced hypotension and cardiac modifications. In: Braquet, P, editor. Ginkolides: Chemistry, Biology, Pharmacology and Clinical Perspectives. New York; 365-375.

  28. YASUDA, K., M. TAKASHIMA, and I. SAWARAGI. 1995. Influence of cigarette smoke extract on the hormonal regulation of PAF acethylhydrolase in rats. Biol. Reprod. 53:244-252.

    Google Scholar 

  29. THOMAS, T. K., R. S. CHESONIS, D. SCHMOLZE, J. SYMINGTON, M. L. HARBISON, A. WALSER, and P. C. WILL. 1993. Differential antagonism of PAF-induced neutrophilia and gastric hemorrhage in the rat. Agents & Actions 39:C195-C197.

    Google Scholar 

  30. REGOLI, D., and J. BARABE. Pharmacology of bradykinin and related kinins. 1980. Pharmacol. Rev. 32:1-46.

    Google Scholar 

  31. HOSHIKAWA-FUJIMURA, A. Y., J. O. AULER, T. R. DA ROCHA, L. I. BRANDIZZI, J. M. PASCUAL, D. A. CHAMONE, and A. D. JATENE. 1989. PAF-aceter, superoxide anion and β-glucuronidase as parameters of polymorphonuclear cell activation associated with cardiac surgery and cardiopulmonary bypass. Braz. J. Med. Biol. Res. 22:1077-1182.

    Google Scholar 

  32. RUVOLO, G., G. SPEZIALE, E. GRECO, L. TRITAPEPE, V. MOLLACE, G. NISTICO, and B. MARINO. 1995. Nitric oxide release during hypothermic versus normothermic cardiopulmonary bypass. Eur. J. Cardio. Thor. Surg. 9:651-654.

    Google Scholar 

  33. EZEAMUZI, J. C., and A. C. NJOKU. 1992. The role of neutrophils in acute and chronic inflammation in rats. Afr. J. Med. Med. Sci. 21:23-28.

    Google Scholar 

  34. TEPPERMAN, B. L., B. L. VOZZOLO, and B. D. SOPER. 1993. Effect of neutropenia on gastric mucosal integrity and mucosal nitric oxide synthesis in the rat. Dig. Dis. Sci. 38:2056-2061.

    Google Scholar 

  35. POJDA, S. M., and J. R. VANE. 1971. Inhibitory effects of aprotinin on kallikrein and kininases in dog' blood. Br. J. Pharmacol. 42:558-568.

    Google Scholar 

  36. MURKIN, J. M. 1994. Tranexamic acid is not better than aprotinin in decreasing bleeding after cardiac surgery. J. Cardiothor. Vasc. Anes 8:474-476.

    Google Scholar 

  37. CORBEAU, J. J., J. P. MONRIGAL, J. P. JACOB, C. COTTINEAU, X. MOREAU, J. G. BUKOWSKI, J. B. SUBAYI, and A. DELHUMEAU. 1995. Comparison of effects aprotinin and tranexamic acid on blood loss in heart surgery. Ann. Fran. Anesth. Reanim. 14:154-161.

    Google Scholar 

  38. BOUGHENOU, F., S. MADI-JEBARA, S. MASSONNET-CASTEL, L. BENMOSBAH, A. CARPENTIER, and M. T. COUSIN. 1995. Fibrinolytic inhibitors and prevention of bleeding in cardiac valve surgery. Comparison of tranexamic acid and high dose aprotinin. Arch. Mal. Coeur Vais. 88:363-370.

    Google Scholar 

  39. GUENTHER, C. R. 1994. Tranexamic acid is better than aprotinin in decreasing bleeding after cardiac surgery. J. Cardiothor. Vasc. Anes. 8:471-473.

    Google Scholar 

  40. ZEHR, K. J., R. S. POSTON, P. C. LEE, K. UTHOFF, P. KUMAR, P. W. CHO, A. M. GILLINOV, J. M. REDMOND, J. A. WINKELSTEIN, and A. Herskowitz. 1995. PAF inhibition reduces lung injury after CPB. Annals Thor. Med. 59:328-335.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, Sherbrooke, P.Q., Canada, J1H 5N4

    Jeannick G. O'Brien, Bruno Battistini, Gérard E. Plante & Pierre Sirois

  2. Department of Anaesthesia, Faculty of Medicine, University of Sherbrooke, Sherbrooke, P.Q., Canada, J1H 5N4

    FrançCoise Zaharia

Authors
  1. Jeannick G. O'Brien
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bruno Battistini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. FrançCoise Zaharia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gérard E. Plante
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pierre Sirois
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

O'Brien, J.G., Battistini, B., Zaharia, F. et al. Effects of Tranexamic Acid and Aprotinin, Two Antifibrinolytic Drugs, on PAF-induced Plasma Extravasation in Unanesthetized Rats. Inflammation 24, 411–429 (2000). https://doi.org/10.1023/A:1007060011553

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1007060011553

Keywords

Search

Navigation